In both humans and mice, Foxp3+ regulatory T (Treg) cells are required to suppress self-reactive T cells and prevent autoimmunity. In addition to this suppressor function, Treg cells are also present in non-lymphoid tissues, where they may utilize distinct transcriptional programs to perform tissue-specific functions. However, a molecular understanding of tissue Treg development and function remains elusive. To address the properties and functions of Treg cells in non-lymphoid tissues, I have examined the transcriptome of hepatic Treg cells by RNA sequencing. By comparing highly expressed genes in hepatic Treg cells to previously generated gene expression data of Treg cells from adipose tissue and colon, I have identified the nuclear receptor ROR? as being enriched in Treg cells from these three peripheral tissues. Subsequently, I will define the role of ROR? in Treg cells by extensively characterizing conditional knockout mice in which Treg cells lack ROR?. I will use genetic tools and a candidate approach to identify the molecular signals that regulate ROR? expression, and RNA sequencing to identify the genes regulated by ROR? in Treg cells. Using the liver as a model organ for its unique capacity for regeneration, I will examine the role of Tre cells in the setting of necro-inflammatory liver damage versus compensatory hyperplasia. I will use conditional knockout mice in which Treg cells lack ROR? or other tissue-Treg-specific molecules, or Foxp3DTR mice in which Treg cells can be depleted, to determine the functional significance of Treg cells in tissue repair. Tissue Treg cells are an attractive candidate for immunomodulation in the therapy of many autoimmune, infectious, metabolic, and neoplastic diseases. By advancing basic knowledge of the mechanisms governing tissue Treg function, the proposed research may reveal novel strategies for immunotherapy.